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Genetic Testing for Primary Lymphedema
FLT4 (also known as VEGFR3) FOXC2, SOX18, HGF, and MET, have been identified as the cause of primary lymphedema. However, clinical genetic testing is currently available only for FLT4, SOX18, and FOXC2. (See diagram of FOXC2 to the right).
Clinical testing for all three of these genes is available at Prevention Genetics in Wisconsin and for FLT4 and FOXC2 only at SW Thames Molecular Genetics Diagnostic Laboratory in London (see contact information below).
The cost for genetic testing depends on both the size of the gene and whether a familial mutation (change) has already been identified or if the entire gene must be screened, and can therefore range from $200* to $1500*. Clinical testing, which is not provided directly to patients, is only offered through physicians, geneticists, or genetic counselors.
Genetic counseling is advised and often required before genetic testing can be performed so that patients can be apprised of the benefits and limitations to genetic testing for their condition.
In addition, several research studies, including the Lymphedema Family Study at the University of Pittsburgh (see contact information below), continue to search for additional lymphedema genes in families with an extensive history of primary lymphedema at no cost to the participating families. As part of their research, these studies often screen families for mutations in ALL five of the previously identified lymphedema genes, as well as many other possible lymphedema genes. Although these research results will take longer to receive from a research lab than a clinical lab, and they cannot be used for medical decision-making, the research results can typically be confirmed by a clinical laboratory for a reduced fee.
FLT4 mutations cause congenital onset (present from birth) primary lymphedema, also known as Milroy’s Disease. Milroy’s Disease is characterized by swelling of the lower extremities, and occasionally the scrotum in males, which is present at birth or develops within the first few years of life. Milroy’s Disease exhibits dominant inheritance, meaning that individuals with an FLT4 mutation have a 1 in 2 (50%) chance of passing that mutation on to each child, theoretically leading to lymphedema. However, only about 85-90% of those who inherit an FLT4 mutation will actually develop lymphedema, a phenomenon called incomplete penetrance. In addition, Milroy’s Disease also exhibits variable expression, which means that there can be differing levels of severity of the lymphedema in different family members. FLT4 is the gene that codes for the production of vascular endothelial growth factor receptor 3 (VEGFR3), which is important in normal growth and development of the lymphatic vessels. Mutations in certain critical regions of FLT4, called the tyrosine kinase domains, cause impaired signaling from the VEGFR3 receptor, and result in hypoplasia (underdevelopment) of the lymphatic vessels. FLT4 consists of 31 exons (coding regions). However, most mutations in the FLT4 gene have been found in 8-10 of these exons, and therefore, sequencing of this gene can initially be targeted to these areas, reducing the cost of screening to approximately $500*. If no mutation in these exons is identified, the remaining exons can be screened by Prevention Genetics for an additional charge of approximately $1,000*.
MUTATIONS IN THE FOXC2 GENE
Mutations in the FOXC2 gene cause the Lymphedema-Distichiasis (LD) Syndrome, which consists of lymphedema and distichiasis (double rows of eyelashes). The lymphedema is often confined to the lower extremities, is asymmetric, and has a variable age of onset. The swelling, however, usually develops around puberty in both males and females, or during pregnancy in females. Other features such as ptosis (droopy eyelids), and less common features such as heart defects or cleft palate, have been observed in LD. Like Milroy’s Disease, LD also has dominant inheritance with variable expression and incomplete penetrance. FOXC2 codes for a protein that regulates the activity of several other genes that are involved in the development of several organs and systems in the fetus. FOXC2 is a much smaller gene than FLT4, containing only one exon, and is therefore less costly than FLT4 for genetic testing (approximately $200-400*). Most mutations in FOXC2 result in a protein product that is unable to effectively regulate the activity of certain genes involved in the development of the lymphatic system and other areas affected by the LD Syndrome.
SOX18 mutations cause the rare Lymphedema-Hypotrichosis-Telangiectasia Syndrome. Lymphedema, which is of the lower extremities and occasionally the eyelids and scrotum, is of variable onset, but usually develops by puberty if not present at birth. Hypotrichosis (sparse hair) is usually apparent by age 1 and can manifest with absent eyebrows and eyelashes. Telangiectasias, red spots caused by dilated blood vessels, can be found on the legs, feet, hands, scrotum, and scalp.
Although Milroy’s Disease (FLT4) and LD Syndrome (FOXC2) both exhibit only dominant inheritance, Lymphedema-Hypotrichosis-Telangiectasia Syndrome has been observed in both dominant and recessive inheritance patterns. Recessive inheritance means that the disease only occurs when a double dose (2 copies) of a mutated gene are inherited, with one dose (copy) inherited from each parent. Carriers of recessive diseases, who have only one copy of the mutated gene, do not have the disease. However, 2 carrier parents have a 1 in 4 (25%) chance with each pregnancy that the child will inherit the mutated gene from each of them, leading to a double dose of the mutated gene and transmission of the disease. Because the gene is small, with only 2 exons, it is approximately $500* to screen.
Information about prenatal genetic testing is available on the website www.preventiongenetics.com through Prevention Genetics, and is only for families with a previously identified mutation in FLT4 or FOXC2. However, genetic counseling would be required before testing could be performed so that parents can be completely informed about the limitations of prenatal genetic testing. Although prenatal genetic testing is the only certain method of determining whether a fetus carries a familial FLT4 or VEGFR3 mutation, both Milroy’s Disease and LD Syndrome exhibit reduced penetrance and variable expression, which could result in a positive mutation result for a baby with no or minimal lymphedema. Therefore, targeted ultrasound with views of the neck, legs, feet, and potentially other body parts, such as the hands, scrotum, and abdomen, would be a necessary complimentary technique for determining both the presence and the severity of congenital lymphedema. In most cases, however, targeted ultrasound could be used as a stand-alone diagnostic tool, especially for severe cases of Milroy’s Disease.
For more information please visit our website at http://www.hgen.pitt.edu/projects/lymph/
* These genetic testing prices were effecive, as of 2/1/10, and are subject to change at any time.
CLINICAL GENETICS TESTING CENTERS FOR LYMPHEDEMA
Department of Medical Genetics
RESEARCH GENETICS TESTING CENTERS FOR LYMPHEDEMA:
Lymphedema Family Study
Lymph Notes thanks Kara Levine, M.S. who is a Genetic Counselor with the “Lymphedema Family Study” at the University of Pittsburgh for writing this helpful article in 2010.
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